Autoimmune Polyendocrinopathy Ectodermal Dystrophy (APECED) is an autosomal recessively inherited autoimmune disorder. The culprit gene, termed Autolmmune Regulator (AIRE), for this syndrome was recently positionally cloned and has afforded a unique opportunity to study the mechanism by which defects in this gene lead to autoimmunity. Preliminary studies have indicated that the gene is primarily expressed in the medulla of the thymus in a unique subset of epithelial cells in this compartment. The hypothesis of this proposal is that the AIRE gene influences the selection of T cells in the thymus and a defect in this gene leads to the autoimmunity seen in APECED patients. There are three major aims of this work. The first is to develop an animal model of APECED by knocking out the gene in mice and to characterize these mice. A second aim is to examine how the AIRE gene influences T cell selection in the thymus. The final aim is to examine the effects of genetic background and environment on the phenotype of APECED. The candidate in this proposal is a clinical endocrinology fellow with expertise in the general field of immunology. The candidate's goals are to develop a research project that utilizes skills in both fields and expands his knowledge in both fields to position himself for scientific independence. The candidate's long term goal is to run an independent laboratory in an academic setting where 90 percent of his time is devoted to the laboratory and 10 percent of his time is devoted to teaching and clinical work. The laboratory that the proposed work will occur in has a well-established track record in the field of immune tolerance and autoimmunity and will provide an excellent environment for the candidate to pursue these studies.